| In recent years,other countries,including China,the number of diabetic patients increased rapidly at an alarming rate.Diabetes has become a major medical challenges in clinical therapy and the number one killer of human health.Diabetic vascular disease is one of the chronic complications of diabetes,involves all important organs of the whole body.It mainly divided into macrovascular diseases and microvascular diseases.The macrovascular diseases,such as atherosclerosis,dysfunction of vasodilation or vasoconstriction and proliferation of vascular smooth muscle.The microvascular diseases mainly include diabetic cardiomyopathy,diabetic retinopathy and diabetic nephropathy(DN).DN is a general term for chronic kidney disease which is caused by hyperglycemia and is a serious complication of diabetes mellitus.Although intensive management of diabetes mellitus through concurrent control of glucose,lipids and blood pressure,can slow the progression of diabetic nephropathy,diabetes mellitus remains the most common cause of end-stage renal disease(ESRD).Diabetes causes vascular endothelial cell injury and apoptosis,endothelial dysfunction as well as the destruction of vascular endothelial integrity and vascular function,thus directly leading to the occurrence of vascular diseases.At present,more and more studies confirm that endothelial dysfunction is the earliest and most fundamental pathological change in diabetes,and is responsible for many cardiovascular complications.Recent studies have found that the dysfunction of glomerular vascular endothelial cells plays a critical role in the development and progression of DN.Conventional wisdom is that diabetes causes tissue damage through four major mechanisms:increased flux of glucose and other sugars through the polyol pathway,increased intracellular formation of advanced glycation end-products(AGEs)and increased expression of the receptor for advanced glycation end products(AGEs)and its activating ligands,activation of protein kinase C(PKC)isoforms,overactivity of the hexosamine pathway.However,the protective effect of blocking one or two of these pathways is not ideal.Several lines of evidence indicate that all four mechanisms are activated by a single upstream event:mitochondrial overproduction of reactive oxygen species.Therefore,the unified mechanism of chronic complications of diabetes mellitus with mitochondrial oxidative stress(mtROS)as the central link has been paid more and more attention by researchers.Mitophagy comes under selective autophagy following which the impaired mitochondria are engulfed by autophagosome for their degradation by lysosome(the process of selective removal of damaged mitochondria).As a mechanism of endogenous resistance to oxidative stress,mitophagy plays an important role in improving oxidative stress in cells,and has attracted more and more attention in recent years.When mitochondria encounter oxidative stress,they become dysfunctional leading to arrest in mitochondrial dynamics where mitophagy comes into action to turn over the dysfunctional organelle and reduce mtROS level.This research will mainly focus on mitochondrial oxidative stress and mitophagy in glomerular vascular endothelial cells,elucidating their roles in the development and progression of DN and discussing the application and mechanism of mitophagy as a starting point to alleviate mtROS in ameliorating diabetes induced glomerular vascular endothelial injury.Objective:In vivo and in vitro studies have found that CoQ10 has strong antioxidant damage which mainly targets mitochondria.It can significantly alleviate the renal mitochondrial dysfunction caused by diabetes mellitus via anti-ROS effect,thus playing a good role in renal protection,gradually become a hot spot in the study of diabetes mellitus and its vascular complications.This study aimed to focus on the mtROS and mitophagy to elucidate the specific molecular mechanism of CoQ10 in exerting its protective role against diabetes-induced glomerular endothelial impairment.Methods and results:db/db mice were treated with CoQ10,which was mixed with feed.Murine glomerular endothelial cells(mGECs)were cultured either in normal glucose(NG 5.5 mM)or high glucose(HG,33 mM)medium in the presence or absence of CoQ10 for 72 h.1.CoQ10 significantly attenuated diabetes-induced renal function damage,glomerular pathological and morphological changes and apoptosis in glomeruli of db/db mice;CoQ10 co-treatment well decreased the apoptosis level of mGECs.2.Diabetes-induced mGECs and glomeruli of db/db mice to generate excessive mtROS and reduce mitophagy,impair mitochondrial function and oxidative stress occur.CoQ10 significantly promoted mitophagy,meanwhile attenuated diabetes-induced excessive mtROS generation and alleviated mitochondrial dysfunction.3.In the presence of PINK1 siRNA to interfere with the expression of mitophagy promoter PINK1 in mGECs,largely attenuated CoQ10-modulated endothelial protective effects against diabetes.Inhibition or activation of mitophagy separately by Mdivi-1 or Torin 1 in vivo,confirmed that CoQ10 attenuated diabetes-induced renal function damage,glomerular pathological and morphological changes and apoptosis in glomeruli of db/db mice were associated upregulation of mitophagy.4.In the presence of Nrf2 siRNA to interfere with the expression of Nrf2 in mGECs in vitro,and inhibition of Nrf2/ARE pathway by ML385 in vivo,both greatly counteracted CoQ10-activated mitophagy effect.5.In the presence of Nrf2 siRNA to interfere with the expression of Nrf2 in mGECs,largely attenuated CoQ10-modulated endothelial protective effects against diabetes.Inhibition Nrf2/ARE pathway by ML385 in vivo,greatly counteracted CoQ10-modulated renal protective effect.Conclusions:Diabetes-induced excessive mtROS plays a detrimental role in glomerular endothelial cells.CoQ10 treatment restores diabetes-impaired mitophagy activity to participate in negative regulation of mitochondrial ROS synthesis.This machinery is performed through activating Nrf2/ARE pathways. |
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